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Reply from the authors

Edward A.Neuwelt, Oregon Health & Science University

Published April 01, 2011

We thank Dr. Chamberlain for his comments regarding our article. The first issue concerns drug delivery. Studies are not available showing that bevacizumab directly decreases or increases drug delivery in the CNS.

Careful quantitative drug delivery studies must be performed in animal models and humans to show that gadolinium based contrast agent permeability seen on MRI actually corresponds to delivery of other low molecular weight agents such as temozolomide. As we indicated, bevacizumab and carboplatin appeared to have a synergistic effect in a rat model of glioma. [6] However, rats died with larger tumors suggesting that at least part of the survival increase was due to decreased edema. Similarly, the recent study by Lai et al. in patients that received up-front bevacizumab for GBM demonstrated an increase in progression free survival (PFS) without an increase in overall survival (OS) [5] that may be due to decreased edema.

The second issue is tumor invasion. Dr. Chamberlain suggests that four articles provide evidence that bevacizumab does not increase invasion. In our view, that conclusion is not clear. Other authors have shown that bevacizumab increases invasion [7] and tumor invasion can occur via angiogenic proteins. [8] The issue is not invasion but primarily permeability, concomitant chemotherapy delivery, and inflammation.

The final issue is pseudoprogression, an intense inflammatory response that may be beneficial to patients. Pseudoprogression was rarely seen after up-front bevacizumab in GBM. [5] We suggest this was due to the decreased permeability effect of bevacizumab. Dr. Chamberlain suggests that this decreased incidence of pseudoprogression did not appear to diminish OS, which he primarily attributes to the impact of MGMT promoter methylation in patients. That is an interesting hypothesis but in our view, inflammatory response is vital to the synergism between radiation therapy and temozolomide chemotherapy. In the study by Lai et al., up-front bevacizumab did decrease OS (albeit, not significantly) from 21.1 months to 19.6 months. [5] This effect was particularly apparent in patients under 50 years old and with lower recursive partitioning analysis (RPA) class, [5] groups who typically have the best outcomes in GBM trials.

We agree with Dr. Chamberlain that bevacizumab represents an improvement in the treatment of GBM, but argue that this is only true in progressive disease. Until a survival advantage is demonstrated in treating GBM up front with bevacizumab, there is no clear role for its use in this setting.